Objective: To examine whether long-term measures of cortisol predict Alzheimer disease (AD) risk.Method: We used a prospective longitudinal design to examine whether cortisol dysregulation was related to AD risk. Participants were from the Baltimore Longitudinal Study of Aging (BLSA) and submitted multiple 24-hour urine samples over an average interval of 10.56 years. Urinary free cortisol (UFC) and creatinine (Cr) were measured, and a UFC/Cr ratio was calculated to standardize UFC. To measure cortisol regulation, we used within-person UFC/Cr level (i.e., within-person mean), change in UFC/Cr over time (i.e., within-person slope), and UFC/Cr variability (i.e., within-person coefficient of variation). Cox regression was used to assess whether UFC/Cr measures predicted AD risk.Results: UFC/Cr level and UFC/Cr variability, but not UFC/Cr slope, were significant predictors of AD risk an average of 2.9 years before AD onset. Elevated UFC/Cr level and elevated UFC/Cr variability were related to a 1.31-and 1.38-times increase in AD risk, respectively. In a sensitivity analysis, increased UFC/Cr level and increased UFC/Cr variability predicted increased AD risk an average of 6 years before AD onset. Cortisol dysregulation is commonly found in patients with Alzheimer disease (AD) 1-5 and has been related to AD pathology in animals and humans. 4,[6][7][8][9][10] In rodent models, glucocorticoid increases have preceded b-amyloid (Ab) plaques and tau phosphorylation (for review, see references 7 and 8). Glucocorticoid treatment in nonhuman primates has been associated with increases in more pathogenic (Ab 42 ) relative to less pathogenic (Ab 40 ) Ab species. 9 In patients with AD, elevations in baseline cortisol have predicted AD progression, 4,6 and in cognitively normal and older adults with AD, higher cortisol has been related to increased Ab brain burden.
10Despite these findings, few prospective longitudinal studies have investigated whether cortisol dysregulation precedes AD. The Rotterdam Study found no significant association between baseline cortisol and risk of incident dementia or AD 7.1 years (range 0.1-9.6 years) later in 243 adults (mean age 72 years).11 These findings are limited, however, by the assessment of cortisol at only one time on 1 day.The current study measured 24-hour urinary free cortisol (UFC) from a mean of 4.3 (range 2-12) samples per person spanning a follow-up interval of 10.56 years (range 1-31 years) to examine cortisol regulation as a predictor of AD onset. UFC was collected from 1,025